The development of potential new fluorine-18 labelled radiotracers for imaging the GABAA receptor

Jackson, Alexander; Guilbert, Bénédicte; Plant, Stuart D.; Goggi, Julian; Battle, Mark; Woodcraft, John L.; Gaeta, Alessandra; Jones, Clare; Bouvet, Denis; Jones, Paul A.; O'shea, D. M.; Zheng, Penny Hao; Brown, Samantha; Ewan, Amanda L.; Trigg, William

doi:10.1016/j.bmcl.2012.11.066

Cited by 18 publications

(4 citation statements)

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“…Compared to [ 18 F]AH114726 or [ 11 C]FMZ, [ 18 F]GEH120348 showed higher initial brain uptake but very different pharmacokinetics, with continued accumulation of radioactivity into the cortical regions of high GABA/BzR concentrations and very little clearance from the regions of low receptor densities (striatum, cerebellum) (Figure 4). It can be reasoned that the higher initial brain uptake of [ 18 F]GEH120348 is due to increased lipophilicity (log D 7.4 values: FMZ, 1.12; AH114726, 0.69; GEH120348, 1.62)[13]. The slower clearance of [ 18 F]GEH120348 might be attributed to the higher binding affinity when compared with [ 18 F]AH114726 (K i values: FMZ, 1.3 nM; AH114726, 5.5 nM; GEH120348, 0.76 nM), or due to a combination of differences in affinity and lipophilicity.…”

Section: Discussionmentioning

confidence: 99%

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Novel fluorine-18 PET radiotracers based on flumazenil for GABAA imaging in the brain

Rodnick

Hockley

Sherman

et al. 2013

Nuclear Medicine and Biology

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Introduction Two 7-fluoroimidazobenzodiazepines (AH114726 and GEH120348), analogs of flumazenil, were labeled with fluorine-18 and evaluated as alternative radioligands for in vivo imaging of the GABAA/benzodiazepine receptor by comparing them to [11C]flumazenil in rhesus monkey. Methods Radiotracers were prepared from the corresponding nitro-precursors in an automated synthesis module, and primate imaging studies were conducted on a Concorde MicroPET P4 scanner. The brain was imaged for 60 (12 × 5 min frames) or 90 min (18 × 5 min frames), and data was reconstructed using the 3D MAP algorithm. Specificity of [18F]AH114726 and [18F]GEH120348 was confirmed by displacement studies using unlabeled flumazenil. Results [18F]GEH120348 and [18F]AH114726 were obtained in 13–24% yields (end of synthesis) with high chemical (>95%) and radiochemical (>99%) purities, and high specific activities (2061 ± 985 Ci/mmol). The in vivo pharmacokinetics of [18F]AH114726 and [18F]GEH120348 were determined in a non-human primate and directly compared with [11C]flumazenil. Both fluorine-18 radioligands showed time-dependent regional brain distributions that correlated with the distribution of [11C]flumazenil and the known concentrations of GABAA/benzodiazepine receptors in the monkey brain. [18F]AH114726 exhibited maximal brain uptake and tissue time-radioactivity curves that were most similar to [11C]flumazenil. In contrast, [18F]GEH120348 showed higher initial brain uptake but very different pharmacokinetics, with continued accumulation of radioactivity into the cortical regions of high GABA/benzodiazepine receptor concentrations and very little clearance from the regions of low receptor densities. Rapid washout of both radiotracers occurred upon treatment with unlabeled flumazenil. Conclusion The ease of the radiochemical synthesis, together with in vivo brain pharmacokinetics most similar to [11C]flumazenil, support that [18F]AH114726 is a suitable option for imaging the GABAA receptor.

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Section: Discussionmentioning

confidence: 99%

“…al. reported a lengthy series of new FMZ analogs suitable for fluorine-18 labeling [13]. Of particular interest were the analogs where the fluorine substituent was moved from the 8- to the 7-position (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Novel fluorine-18 PET radiotracers based on flumazenil for GABAA imaging in the brain

Rodnick

Hockley

Sherman

et al. 2013

Nuclear Medicine and Biology

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“…Flumazenil PET was one of the fi rst applications of this approach, and the study of two presymptomatic individuals provided evidence for an early defi cit in GABA A receptor function in the left operculum region (Turner et al 2005b ). Novel GABA A receptor radioligands with longer half-lives may offer broader applicability of PET to study at least one potentially important pathogenic mechanism (Jackson et al 2013 ). Re-evaluation of the serotonergic system using PET in the post-FTD-linked era of ALS, as well as the application of novel neuroinfl ammatory PET ligands (Chauveau et al 2009 ;Chauveau et al 2011 ) might also identify novel therapeutic targets.…”

Section: The Futurementioning

confidence: 98%

Amyotrophic Lateral Sclerosis

Turner¹

2014

PET and SPECT in Neurology

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The core of the clinical syndrome of amyotrophic lateral sclerosis (ALS) is a progressive and typically rapid degeneration of a previously normally functioning motor system, comprising upper motor neurons (UMNs) of the primary motor cortex and corticospinal tract (CST), brainstem nuclei and the lower motor neurons (LMNs) arising from the anterior horns of the spinal cord. Weakness, with variable wasting, of the musculature of the limbs and of speech and swallowing ensues, with involvement of the diaphragm resulting in respiratory insuffi ciency and a median survival of 3 years. The marked clinical heterogeneity, frequent diagnostic delay and reliance of therapeutic trials on survival as the primary outcome measure make the discovery of biomarkers in ALS a research priority.Whilst the spinal anterior horns and corticospinal tract superfi cially appear to bear the brunt of histopathology in ALS, it has been clear for over half a century that degeneration extends to involve the extra-motor brain, preferentially involving areas of the frontal and temporal lobes having clinical and genetic overlap with some forms of frontotemporal dementia (FTD).

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“…The FASTlab™ synthesiser was developed by GE Healthcare for the automated production of [ 18 F]fluorine radiotracers. The synthesiser was designed to aid PET radiopharmaceutical manufacturers to comply with the GMP requirements for PET radiopharmaceuticals . The disposable, single‐use cassette, removes the need to validate a cleaning protocol as the disposable fluid path removes any potential for cross contamination between productions.…”

Section: Clinical Production Of [18f]ge‐179 Using the Fastlab™ Synthementioning

confidence: 99%

Development of an automated, GMP compliant FASTlab™ radiosynthesis of [¹⁸F]GE‐179 for the clinical study of activated NMDA receptors

Khan¹,

Berg

Brown³

et al. 2020

Labelled Comp Radiopharmac

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N‐(2‐chloro‐5‐(S‐2‐[18F]fluoroethyl)thiophenyl)‐N'‐(3‐thiomethylphenyl)‐N'‐methylguanidine, ([18F]GE‐179), has been identified as a promising positron emission tomography (PET) ligand for the intra‐channel phencyclidine (PCP) binding site of the N‐methyl‐D‐aspartate (NMDA) receptor. The radiosynthesis of [18F]GE‐179 has only been performed at low radioactivity levels. However, the manufacture of a GMP compliant product at high radioactivity levels was required for clinical studies. We describe the development of a process using the GE FASTlab™ radiosynthesis platform coupled with HPLC purification. The radiosynthesis is a two‐step process, involving the nucleophilic fluorination of ethylene ditosylate, 11, followed by alkylation to the deprotonated thiol precursor, N‐(2‐chloro‐5‐thiophenol)‐N'‐(3‐thiomethylphenyl)‐N'‐methyl guanidine, 8. The crude product was purified by semi‐preparative HPLC to give the formulated product in an activity yield (AY) of 7 ± 2% (n = 15) with a total synthesis time of 120 minutes. The radioactive concentration (RAC) and radiochemical purity (RCP) were 328 ± 77 MBq/mL and 96.5 ± 1% respectively and the total chemical content was 2 ± 1 μg. The final formulation volume was 14 mL. The previously described radiosynthesis of [18F]GE‐179 was successfully modified to deliver an process on the FASTlab™ that allows the manufacture of a GMP quality product from high starting radioactivitity (up to 80 GBq) and delivers a product suitable for clinical use.

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The development of potential new fluorine-18 labelled radiotracers for imaging the GABAA receptor

Cited by 18 publications

References 27 publications

Novel fluorine-18 PET radiotracers based on flumazenil for GABAA imaging in the brain

Novel fluorine-18 PET radiotracers based on flumazenil for GABAA imaging in the brain

Amyotrophic Lateral Sclerosis

Development of an automated, GMP compliant FASTlab™ radiosynthesis of [¹⁸F]GE‐179 for the clinical study of activated NMDA receptors

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The development of potential new fluorine-18 labelled radiotracers for imaging the GABAA receptor

Cited by 18 publications

References 27 publications

Novel fluorine-18 PET radiotracers based on flumazenil for GABAA imaging in the brain

Novel fluorine-18 PET radiotracers based on flumazenil for GABAA imaging in the brain

Amyotrophic Lateral Sclerosis

Development of an automated, GMP compliant FASTlab™ radiosynthesis of [18F]GE‐179 for the clinical study of activated NMDA receptors

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Development of an automated, GMP compliant FASTlab™ radiosynthesis of [¹⁸F]GE‐179 for the clinical study of activated NMDA receptors